Autoimmune disorders, collectively, affect approximately 5% of the population in Western countries and are a major cause of disability. This group of diseases includes a wide variety of conditions with differing clinical presentations and natural histories. There is compelling evidence for the involvement of both genetic and non-genetic influences, and females are disproportionately affected. Despite decades of intensive investigation, the etiology of autoimmune disease is unknown. A role for microchimerism (MC) and maternal-fetal HLA relationships has been proposed for autoimmunity. Bi-directional cell traffic between mother and fetus occurs during pregnancy, and these fetal cells have been found to persist long-term in the maternal circulation. Strong evidence suggests that this non-host exposure occurring during fetal development, and perhaps through long term persistence of fetal cells in the mother, is biologically relevant, and may play a role in autoimmune disease pathogenesis. HLA sharing or compatibility between mother and offspring may mediate this process, and may also operate in other ways to influence disease risk or clinical outcome. We propose a large, comprehensive and multi-analytical approach to determine whether non-inherited maternal-fetal HLA mechanisms are risk factors in three common HLA-associated autoimmune diseases for which women are at greater risk: multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We will study the influence of fetally derived (paternal) class II HLA alleles and haplotypes on the mother (who has MS, RA or SLE) using a large number of stringently ascertained patients, controls and other family members for each disease. We will include the use of detailed clinical and reproductive histories and HLA profiling. This application takes advantage of three well-characterized and ongoing collections of MS, RA and SLE families and proposes a novel experimental approach for identifying the underlying etiology of complex autoimmune diseases. The results obtained from this study will provide a strong and much needed foundation for future molecular studies of MC and maternal-fetal relationships in autoimmunity.